2.1 Stomach Cancer
Stomach cancer, otherwise known as gastric cancer, is malignancy of the stomach. It occurs most frequently in people between 50 and 70 years of age and is predominantly a disease of men rather than women (1.7:1 ratio). Stomach cancer is relatively common cause of death in Japan, Chile and Iceland, where the death rate is about five times that in the United States (Correa, 1988, Can Res. 48:3554–60). A United Nation estimate of cancer incidence in 24 world areas in 1980 showed that stomach cancer was the most common cancer when combined data (incidences in both men and women) were reviewed (Parkin et al., 1988, Intl J Can. 41:184–197). Despite the continued decrease in incidence of stomach cancer in the United States, it was estimated that there were about 24,000 new cases in 1994 and approximately 14,000 deaths. Studies propose that the decreased incidence may be related to decreased intake of salted, cured and smoked foods, and the increase of vitamin C intake.
Other risk factors for stomach cancer are family history of gastric cancer, risk factors for stomach cancer are family history of gastric cancer, blood type group A, history of pernicious anemia, history of chronic atrophic gastritis, condition of decreased gastric acid, history of adenomatous gastric polyp, and partial gastrectomy. Helicobacter pylori infection also is clearly associated with stomach cancer (Parsonnet et al., 1991, J Natl Can Inst. 83:640–43). For no apparent reason, the incidence of stomach cancer appears to be greater in countries farther from the equator. Also, in most countries, people of lower socioeconomic class tend to develop the disease more frequently than upper classes.
One of the most difficult aspects of the diagnosis of stomach cancer is the nonspecific nature of the symptoms such as loss of appetite, difficulty in swallowing, vague fullness, vomiting blood, abdominal pain, belching, breath odor, excessive gas and flatus, heartburn, weight loss, and a decline in general health. These symptoms often overlap with classic peptic ulcer disease, making diagnosis challenging. Further, most of these symptoms can be either manifestations of local or distant extensions of the neoplasm or simply attributed to other noncancerous diseases in the upper abdomen. Thus, CBC, biopsy and invasive procedures including upper gastrointestinal (GI) endoscopy, upper GI radiographic examination are usually used to examine suspected patients.
There is a wide variation in prognosis of gastric tumors. Tumors in the distal stomach are more often cured than those in the gastric cardiac or gastroesophageal junction. The depth to which the tumor invades the stomach wall and whether lymph nodes are involved influence the likelihood of cure. In circumstances in which the tumor has spread outside of the stomach, cure is not possible and treatment is directed towards improvement of symptoms.
The World Health Organization has histopathologically classified stomach cancer into ten major groups: (1) adenocarcinoma (M81403), (2) papillary adenocarcinoma (M82603), (3) tubular adenocarcinoma (M82113), (4) mucinous adenocarcinoma (M84803), (5) signet ring cell carcinoma (M84903), (6) adenosquamous carcinoma (M85603), (7) carcinoid tumor (M82403), (8) mixed carcinoid-adenocarcinoma (M82443), (9) small cell carcinoma (M80413) and undifferentiated carcinoma (M80203). (Murphy, Table 17-1). Adenocarcinoma is by far the most common stomach cancer followed by malignant lymphoma, which accounts for 8% of all tumors.
The staging of stomach cancer is based on the revised criteria of TNM staging by the American Joint Committee for Cancer (AJCC) published in 1988. Staging is the process of describing the extent to which cancer has spread from the site of its origin. It is used to assess a patient's prognosis and to determine the choice of therapy. The stage of a cancer is determined by the size and location in the body of the primary tumor, and whether it has spread to other areas of the body. Staging involves using the letters T, N and M to assess tumors by the size of the primary tumor (T); the degree to which regional lymph nodes (N) are involved; and the absence or presence of distant metastases (M)—cancer that has spread from the original (primary) tumor to distant organs or distant lymph nodes. Each of these categories is further classified with a number 1 through 4 to give the total stage. Once the T, N and M are determined, a “stage” of I, II, III or IV is assigned. Stage I cancers are small, localized and usually curable. Stage II and III cancers typically are locally advanced and/or have spread to local lymph nodes. Stage IV cancers usually are metastatic (have spread to distant parts of the body) and generally are considered inoperable.
Today, surgery on the stomach (gastrectomy) remains the only curative treatment and continues to be the major approach for palliation. The major options for surgical restriction of stomach cancer are distal subtotal gastric resection, proximal subtotal resection, or total gastrectomy. Restoration of continuity of the alimentary tract is achieved by anastomosis of the small intestine to the gastric remnant (gastroenterostomy), distal stomach to the esophagus (esophagogastrostomy) or small intestine to esophagus (esophagojejunostomy), with or without a jejunal reservoir. Despite major improvements over the years in both surgery and postsurgical management, overall survival rates remain quite low for all but those with early stomach cancer (Adashek et al., 1979, Ann Surg. 189:6–10). For patients in whom surgery is not an option, chemotherapy or radiation can improve symptoms.
A significant number of patients (60%) have unfavorable findings at the time of celiotomy, such as serosal implants, liver or ovarian metastasis, or metastasis seen in lymph nodes outside the limits of a radical en bloc resection. Palliative resection of stomach cancer is always the preferred procedure in those circumstances and seems to prolong survival. However, palliative nonresectional procedures, such as gastrojejunostomy, gastrostomy, or jejunostomy rarely alleviate symptoms or prolong life expectancy.
The use of radiation therapy as a single modality in the definitive treatment of stomach cancer has met with little success despite efforts to increase the total dose to the tumor and reduce the amount of irradiated normal tissue. Radiation therapy is rarely helpful in patients with stomach cancer that is unsuitable for resection, as the usual reason for nonresectability is the lack of anatomic localization of the cancer. Radiation therapy is sometimes used to relieve localized obstruction, particularly in the region of the cardia, and for patients with chronically bleeding cancers that cannot be resected. The median survival for patients treated with radiation is around 12 months, and long-term survivors are few (Beatty et al., 1979, Cancer 43:2254–67; Newaishy et al., 1982, Clin Radiol. 33:347–352; Schuchman et al., 1980, J Thorac Cardiovasc Surg. 79:67–73).
Many chemotherapeutic drugs have been tried in the past as single agents for the palliation of stomach cancer, but the results were generally disappointing. Nevertheless, the role of chemotherapy in the management of stomach cancer is continually evolving. Oftentimes, chemotherapy with radiation in adjunct to surgery is used. In general, chemotherapy can achieve long-term survival rates of up to 15% to 20%, even in patients with recurrent or metastatic disease (Ali et al., 2000, Oncology 14(8):1223–30). Unfortunately, the high initial response rates to first line chemotherapy does not appear to translate into a survival benefit (Kohno and Kitahara, 2001, Gan To Kagaku Ryoho 28(4):448–53). Moreover, there are many undesirable side effects associated with chemotherapy such as temporary hair loss, mouth sores, anemia (decreased numbers of red blood cells that may cause fatigue, dizziness, and shortness of breath), leukopenia (decreased numbers of white blood cells that may lower resistance to infection), thrombocytopenia (decreased numbers of platelets that may lead to easy bleeding or bruising), and gastrointestinal symptoms like nausea, vomiting and diarrhea. Active chemotherapeutic agents include hydroxyurea, 5-fluorouracil, alfa-2a Interferon, doxorubicin, mitomycin C, cisplatin, etoposide, methotrexate, leucovorin and epirubicin.
The identification of active chemotherapeutic agents against cancers traditionally involved the use of various animal models of cancer. The mouse has been one of the most informative and productive experimental system for studying carcinogenesis (Sills et al., 2001, Toxicol Letters 120:187–198), cancer therapy (Malkinson, 2001, Lung Cancer 32(3):265–279; Hoffman R M., 1999, Invest New Drugs 17(4):343–359), and cancer chemoprevention (Yun, 1999, Annals NY Acad Sci. 889:157–192). Cancer research started with transplanted tumors in animals which provided reproducible and controllable materials for investigation. Pieces of primary animal tumors, cell suspensions made from these tumors, and immortal cell lines established from these tumor cells propagate when transplanted to animals of the same species.
To transplant human cancer to an animal and to prevent its destruction by rejection, the immune system of the animal are compromised. While originally accomplished by irradiation, thymectomy, and application of steroids to eliminate acquired immunity, nude mice that are athymic congenitally have been used as recipients of a variety of human tumors (Rygaard, 1983, in 13th International Cancer Congress Part C, Biology of Cancer (2), pp 37–44, Alan R. Liss, Inc., NY; Fergusson and Smith, 1987, Thorax, 42:753–758). While the athymic nude mouse model provides useful models to study a large number of human tumors in vivo, it does not develop spontaneous metastases and are not suitable for all types of tumors. Next, the severe combined immunodeficient (SCID) mice is developed in which the acquired immune system is completely disabled by a genetic mutation. Human lung cancer was first used to demonstrate the successful engraftment of a human cancer in the SCID mouse model (Reddy S., 1987, Cancer Res. 47(9):2456–2460). Subsequently, the SCID mouse model have been shown to allow disseminated metastatic growths for a number of human tumors, particularly hematologic disorders and malignant melanoma (Mueller and Reisfeld, 1991, Cancer Metastasis Rev. 10(3):193–200; Bankert et al., 2001, Trends Immunol. 22:386–393). With the recent advent of transgenic technology, the mouse genome has become the primary mammalian genetic model for the study of cancer (Resor et al., 2001, Human Molec Genet. 10:669–675).
While surgery, chemotherapeutic agents, hormone therapy, and radiation are useful in the treatment of stomach cancer, there is a continued need to find better treatment modalities and approaches to manage the disease that are more effective and less toxic, especially when clinical oncologists are giving increased attention to the quality of life of cancer patients. The present invention provides an alternative approach to cancer therapy and management of the disease by using an oral composition comprising yeasts.
2.2 Yeast-Based Compositions
Yeasts and components thereof have been developed to be used as dietary supplement or pharmaceuticals. However, none of the prior methods uses yeast cells which have been cultured in an electromagnetic field to produce a product that has an anti-cancer effect. The following are some examples of prior uses of yeast cells and components thereof:
U.S. Pat. No. 6,197,295 discloses a selenium-enriched dried yeast product which can be used as dietary supplement. The yeast strain Saccharomyces boulardii sequela PY 31 (ATCC 74366) is cultured in the presence of selenium salts and contains 300 to about 6,000 ppm intracellular selenium. Methods for reducing tumor cell growth by administration of the selenium yeast product in combination with chemotherapeutic agents is also disclosed.
U.S. Pat. No. 6,143,731 discloses a dietary additive containing whole β-glucans derived from yeast, which when administered to animals and humans, provide a source of fiber in the diet, a fecal bulking agent, a source of short chain fatty acids, reduce cholesterol and LDL, and raises HDL levels.
U.S. Pat. No. 5,504,079 discloses a method of stimulating an immune response in a subject utilizing modified yeast glucans which have enhanced immunobiologic activity. The modified glucans are prepared from the cell wall of Saccharomyces yeasts, and can be administered in a variety of routes including, for example, the oral, intravenous, subcutaneous, topical, and intranasal route.
U.S. Pat. No. 4,348,483 discloses a process for preparing a chromium yeast product which has a high intracellular chromium content. The process comprises allowing the yeast cells to absorb chromium under a controlled acidic pH and, thereafter inducing the yeast cells to grow by adding nutrients. The yeast cells are dried and used as a dietary supplement.
Citation of documents herein is not intended as an admission that any of the documents cited herein is pertinent prior art, or an admission that the cited documents are considered material to the patentability of the claims of the present application. All statements as to the date or representations as to the contents of these documents are based on the information available to the applicant and does not constitute any admission as to the correctness of the dates or contents of these documents.